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Animal model for fatty acid amide-related neurobehaviors

a neurobehavior and animal model technology, applied in the field of animal model of fatty acid amide-related neurobehaviors, can solve the problems of difficult, if not impossible, to assess the pharmacological and physiological activities of fatty acid amides and related compounds, hindering efforts to characterize the pharmacological and physiological function of this endogenous brain,

Inactive Publication Date: 2003-02-27
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the presence of FAAH, therefore, it is difficult, if not impossible to assess the pharmacological and physiological activities of fatty acid amides and related compounds.
The disruption of the FAAH gene results in an inability of the mouse to produce detectable levels of FAAH.
Indeed, the half-life of anandamide in vivo is on the order of minutes, severely hindering efforts to characterize the pharmacological and physiological function of this endogenous brain substance.
As a consequence, the pharmacological administration of catabolically labile transmitters may fail to report on their physiological functions in vivo.
When the animals to be made transgenic are avian, because avian fertilized ova generally go through cell division for the first twenty hours in the oviduct, microinjection into the pronucleus of the fertilized egg is problematic due to the inaccessibility of the pronucleus.
When the animals to be made transgenic are bovine or porcine, microinjection can be hampered by the opacity of the ova thereby making the nuclei difficult to identify by traditional differential interference-contrast microscopy.
In addition, it is also possible to introduce transgenes into the germ line, albeit with low efficiency, by intrauterine retroviral infection of the midgestation embryo (D. Jahner et al., supra).
Peptides and polynucleotides, for example, are not particularly useful when administered orally because they can be degraded in the digestive tract.

Method used

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  • Animal model for fatty acid amide-related neurobehaviors
  • Animal model for fatty acid amide-related neurobehaviors
  • Animal model for fatty acid amide-related neurobehaviors

Examples

Experimental program
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Effect test

example 2

Biochemical Characterization of FAAH Knockout Mice

[0060] This example provides biochemical assays useful for characterizing the FAAH knockout mice.

[0061] Brain and liver were isolated from homozygous wild type (FAAH.sup.+ / +), heterozygous (FAAH.sup.+ / -) and homozygous knockout (FAAH.sup.- / -) mice and examined by western blot analysis using polyclonal anti-FAAH antibodies (see Patricelli et al., Biochemistry 37:15177-15187, 1998). No FAAH protein was detectable in the brain or liver of the knockout mice.

[0062] The mice also were examined for FAAH enzymatic activity. FAAH activity assays for oleamide and anandamide were measured by following the conversion of .sup.14C-labeled substrates using a thin layer chromatography assay essentially as described by Patricelli et al. (Biochemistry 38:9804-9812, 1999), except that enzyme assays were conducted at pH 7.2. Brain and liver from FAAH.sup.- / - mice exhibited greatly reduced FAAH catalytic activity (Table 1). Brain extracts from FAAH.sup.-...

example 3

Neurobehavioral Examination of FAAH Knockout Mice

[0063] This example provides neurobehavioral assays that measure spontaneous activity, thermal pain sensation, catalepsy, and rectal temperature, and demonstrates that FAAH regulates anandamide activity in vivo.

[0064] Experiments were performed using a combination of male and female mice (no significant sex differences were observed for either genotype). All drugs were administered intraperitoneal (ip) in a mixture of 1 part ethanol: 1 part EMULPHOR alcohol (GAF Corp.; New York N.Y.): 18 parts saline (10 .mu.l / g body weight), except naloxone was administered ip in saline.

[0065] Locomotor activity was assessed by placing each mouse in a clear plexiglass cage (18.times.10.times.8.5 inches; l.w.h) that was marked in 7 cm square grids on the floor of the cage. The number of grids that were traversed by the hind paws was counted from 15 to 20 min post-injection. Nociception was assessed using the tail immersion assay, wherein each mouse wa...

example 4

Generation of a Mouse Model with FAAH Expression Restricted to the Nervous System

[0077] Exogenously applied and endogenously produced fatty acid amides induce a variety of behavioral effects in mammals, which may reflect either central or peripheral sites of action. In wild type mammals, FAAH is not only expressed in the central and peripheral nervous system, but also in a variety of non-nervous system peripheral tissues, including liver, kidney, and testis. Thus, a standard deletion of the FAAH gene results in an animal model where FAAH is absent from all sites in the organism and therefore does not permit an assignment of phenotypes to central or peripheral modes of action. To address this issue, the mouse FAAH cDNA was placed under the control of the neural specific enolase (NSE) promoter (Forss-Petter et al. (1990) Neuron 5, 187-197) and this construct was used to generate transgenic mice (mixed background of C57Bl / 6 and Balb / c) by pronuclear injection methods following standard...

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Abstract

The invention relates to an animal model for studying behavior related to fatty acid amide and hydrolysis of fatty acid amide. The invention provides transgenic animals in which the protein fatty acid amide hydrolase is not expressed, and methods of using such animals.

Description

[0001] This application claims priority under 35 U.S.C. .sctn.119(e) to U.S. Provisional Application Serial No. 60 / 309,098 filed Jul. 31, 2001, the contents of which are incorporated herein by reference in its entirety.[0003] The invention relates generally to animal model systems useful for examining and manipulating the half-life of bioactive molecules that influence behavior, and, more specifically, to fatty acid amide hydrolase (FAAH) gene knockout mice and to methods of using the knockout mice to identify agents that alleviates pain or modulate other behaviors.BACKGROUND INFORMATION[0004] The in vivo levels of chemical messengers like the fatty acid amides are tightly regulated to maintain proper control over their influence on brain and body physiology. One mechanism by which the level of fatty acid amides are regulated in vivo is through an enzyme termed fatty acid amide hydrolase (FAAH) which degrades the fatty acid amides to inactive metabolites. FAAH effectively terminates...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K49/00A61P25/00C12N9/16C12N9/80C12N15/55C12N15/85
CPCA01K67/0276A01K2217/072A01K2217/075A01K2227/105A01K2267/03A01K2267/0356A61K49/0008C12N9/16C12N9/80C12N15/8509C12N2830/008A61P25/00
Inventor CRAVATT, BENJAMIN F.
Owner THE SCRIPPS RES INST
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